IGIF Does Not Drive Th1 Development but Synergizes with IL-12 for Interferon-γ Production and Activates IRAK and NFκB

Abstract

In these studies, IFN gamma-inducing factor (IGIF), unlike IL-12, did not drive Th1 development in BALB/c or C57BL/6 mice, but like IL-1alpha, potentiated IL-12-driven Th1 development in BALB/c mice. IGIF and IL-12 synergized for IFN gamma production from Th1 cells. Unlike IL-1alpha, IGIF had no effect on Th2 cells. IGIF signaled through IRAK, IL-1 receptor-associated kinase, to induce nuclear translocation of p65/p50 NFkappaB in Th1 cells. IL-1alpha had no effect on proliferation, cytokine production, or NFkappaB activation in Th1 cells but activated NFkappaB and proliferation in Th2 cells. Thus, Th1 and Th2 cells may differ in responsiveness and receptor expression for IL-1 family molecules. IGIF and IL-1alpha may differentially amplify Th1 and Th2 effector responses, respectively.

IL-12p70 and IL-18 gene-modified dendritic cells loaded with tumor antigen-derived peptides or recombinant protein effectively stimulate specific Type-1 CD4+ T-cell responses from normal donors and melanoma patients in vitro

“…In contrast, DCs infected with either Ad.IL-12 (DC.IL-12) or Ad.IL-18 (DC.IL-18) exhibited immunostimulatory capacities that were no greater than those noted for DCs infected with Ad.C5 (DC.C5). The improved efficacy associated with DC.IL-12/18 stimulator cells may reflect the knowledge that IL-12p70 is required to induce T-cell surface expression of the IL-18R on naı¨ve T cells, 22 whereas the IL-1 family member, IL-18, potentiates the differentiation of Th1 cells instigated by IL-12p70, 23 and that IL-12 and IL-18 synergize in the activation of T cells and induction of IFN-g secretion from T-cell responders. 20,21 To evaluate the efficacy of this approach in the cancer setting, monocyte-derived DCs were generated from eight HLA-DR4 þ melanoma patients and used to stimulate autologous CD4 þ T cells in vitro.…”

“…20,21 IL-12p70 induces T-cell surface expression of the IL-18 receptor (IL-18R) by naı¨ve T cells, 22 whereas IL-18, an IL-1 family member, potentiates the differentiation of Th1 cells instigated by IL-12p70. 23 We hypothesized that dysfunctional antitumor Th1-type responses in cancer patients with active disease might be recovered/enhanced by in vitro stimulation (IVS) of patient CD4 þ T cells using vaccines containing autologous dendritic cells (DCs) engineered to secrete IL-12p70 and/or IL-18. This gene therapy approach could not only prove capable of supporting Type-1 immunity, but would have the potential to obviate toxicities previously observed for systemic application IL-12p70 alone [24][25][26] or IL-12p70 combined with IL-18.…”

cis-Element clustering correlates with dose-dependent pro- and antisignaling effects of IL18

“…This result was in part anticipated based on previous experiments demonstrating IL18-dependent activation of the NFkB pathway. 1,15 We further illustrated dose-dependent activation of NFkB binding using biochemical assays.…”

“…1,2 It is also thought to activate NK cells 3,4 and monocytes, including the myelomonocytic cell line KG-1. 5-10 IL18 signal transduction is mediated via a heterodimeric receptor 11 that engages IRAK via Myd88 [12][13][14] leading to activation of the NFkB pathway 1,15 via NIK, as well as the activation of AP1 via JNK. 13 Whether IL18 receptor engagement activates other pathways, is not known.…”

Linkage analysis of the genetic determinants of T-cell IL-4 secretion, and identification of Flj20274 as a putative candidate gene

“…Thus, the generation of Th1 cells is critically driven by the presence of IL-12, 3 with additional contributions from IL-18. 4 In contrast, the key determinant of Th2 differentiation is the availability of IL-4. 5 The action of these critical cytokines is characterized by reciprocal inhibition of opposing Th subsets and progressive stabilization of developing Th populations.…”